Potassium dicyanoargentate

Endpoint summary

Description of key information

Repeat dose oral toxicity study in rats to test guideline OECD422 standard. Animals were treated daily at dose levels of 1, 3 and 10 mg/kg/day for a total of 29 days for males and 42-46 days for females.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

21 March 2016 - 17 June 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Repeat dose toxicity studies provide information on the possible toxicological effects likely to arise following repeated exposure to a substance. Monitored effects include changes in morphology, physiology, growth or lifespan, behaviour or impairment of capacity to compensate for additional stress. A subacute repeat dose toxicity study (28-days) is required to fulfil REACH Annex VIII information requirements. By default, the route of administration for compliance with Annex VIII is usually oral, unless there are scientific or logistical reasons for using other routes of exposure.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

March 1996

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Version / remarks:

May 2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Identification: Potassium dicyanoargentate
- Form: solid crystals
- Source and lot/batch No.of test material: 112415

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature
- Stability under test conditions:Unknown

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Vehicle: Water (Elix, Millipore S.A.S., Molsheim, France)
- Rationale for vehicle: Trial formulations performed at Charles River Den Bosch
- Formulations: Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenised to a visually acceptable level. No adjustment was made for specific gravity/density of the test item, vehicle, and/or formulation.

FORM AS APPLIED IN THE TEST (if different from that of starting material): Solution

CHEMICAL ANALYSIS OF DOSE PREPARATIONS:
Analyses were conducted on a single occasion during the treatment phrase (11 May 2016) according to a validated method (Test Facility Study No. 510781). Samples and formulations were analysed for homogeneity (highest and lowest concentrations) and accuracy of preparations (all concentrations). The accuracy of preparation was considered acceptable if the mean measured concentrations were 90-110% of the target concentration. Homogeneity was demonstrated if the coefficient was ≤10%.
As a complex metal cyanide, no appropriate analytical method is available, consequently, the concentration was based on detection of silver (Ag).

Species:

rat

Strain:

Wistar

Details on species / strain selection:

Crl: WI (Han) Wistar rats. This species and strain of rat has been recognised as appropriate for general and reproductive toxicity studies. Charles River Den Bosch has general and reproduction/developmental historical control data in this species from the same strain and source. This animal model has been proven to be susceptible to the effects of reproductive toxicants.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Females were supplied by Charles River Deutschland, Sulzfeld, Germany. Males were supplied by Charles River Laboratories, Kingston, NY, USA.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 10-12 weeks
- Weight at study initiation: All animals were within ±20% of the mean per sex. Animals were assigned to groups by computer-generated random algorithm according to body weight.
- Housing: Animals were housed in groups of 5/cage in Macrolon plastic cages (MIV type, height 18 cm) during the pre-test and pre-mating. During mating, females were caged together with one male on a one-to-one basis in Macrolon plastic cages (MIII type, height 18 cm). Post-mating, males were housed in their home cage, whereas females were housed individually in Macrolon plastic cages (MIII type, height 18 cm).
- Diet (e.g. ad libitum): Pelleted rodent diet 9SM R/M-Z from SSNIFF Spezialdiäten GmbH, Soest, Germany) ad libitum
- Water (e.g. ad libitum): Free access to tap-water
- Acclimation period: At least 5 days prior to start of treatment

DETAILS OF FOOD AND WATER QUALITY:
Diet, water, bedding and cage-enrichments/nesting material were evaluated for contaminants and/or nutrients, according to facility standard procedures. There were no findings that could interfere with the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C
- Humidity (%): 40 to 70%
- Air changes (per hr): at least 10 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle

Route of administration:

oral: gavage

Details on route of administration:

Oral gavage, using a plastic feeding tube. Formulations were placed on a magnetic stirrer during dosing. A dose volume of 5 mL/kg body weight, according to the most recent body weight measurement.

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Vehicle: water
- Concentration in vehicle: 0, 1, 3 and 10 mg/kg bw/day
- Amount of vehicle (if gavage): 5 mL/kg bw

CHEMICAL ANALYSIS OF DOSE PREPARATIONS:
Analyses were conducted on a single occasion during the treatment phrase (11 May 2016) according to a validated method (Test Facility Study No. 510781). Samples and formulations were analysed for homogeneity (highest and lowest concentrations) and accuracy of preparations (all concentrations). The accuracy of preparation was considered acceptable if the mean measured concentrations were 90-110% of the target concentration. Homogeneity was demonstrated if the coefficient was ≤10%.
As a complex metal cyanide, no appropriate analytical method is available, consequently, the concentration was based on detection of silver (Ag).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentrations analysed in the formulations of Group 2, 3 and 4, were in agreement of target concentrations (i.e. mean accuracies between 90% and 110%). A small response at m/z 107, possibly of silver, was observed in the Group 1 (i.e. control) formulation. The maximum contribution of the formulation samples based on response was 0.020%, taking the dilution factor into account. The formulations of Group 2 and Group 4 (i.e. the low and high doses), were homogeneous (i.e. coefficient of variation ≤10%).

Duration of treatment / exposure:

Males: 29 days, i.e. 2 weeks prior to mating, during mating, and up to the day prior to scheduled necropsy.

Females: 42-46 days, i.e. 2 weeks prior to mating, during mating, the duration of the pregnancy and at least 13 days after delivery, up to and including the day before scheduled necropsy. Females which failed to deliver healthy offspring were exposed for 42 days. Two females were not dosed on one occasion, as they were littering at the time of dosing. The omission was not considered toxicologically significant over the dosing period.

Frequency of treatment:

Once daily for 7 days per week, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose.

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Group 1 (vehicle control)

Dose / conc.:

1 mg/kg bw/day (nominal)

Remarks:

Group 2

Dose / conc.:

3 mg/kg bw/day (nominal)

Remarks:

Group 3

Dose / conc.:

10 mg/kg bw/day (nominal)

Remarks:

Group 4

No. of animals per sex per dose:

10 Males and 10 Females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Based on the results of a 14-day dose-ranging study (Test Facility study No. 510779), the dose levels for the combined 28-day oral gavage study (OECD 422) were selected to be 1, 3 and 10 mg/kg/day.

- Study outline: Potassium dicyanoargentate, formulated in water, was administered daily by oral gavage to SPF-bred Wistar Han rats. One control group and three treated groups were tested, each consisting of 10 males and 10 females. Males were exposed for 29 days, i.e. 2 weeks prior to mating, during mating and up to termination. Females were exposed for 42-46 days, i.e. 2 weeks prior to mating, during mating, during post-coitum, and 5-6 days of lactation. Females which failed to deliver healthy offspring were exposed for 42 days. Pups were not dosed directly, but could have potentially been exposed to the test item in utero, via maternal milk, or from exposure to maternal urine/faeces.

- Evaluated Parameters: mortality / viability, clinical signs (daily), functional observations and locomotor activity (end of treatment), body weight and food consumption (at least at weekly intervals), clinical pathology (end of treatment), blood sampling for possible exposure control (Day 3 and end of treatment), macroscopy at termination, organ weights and histopathology on a selection of tissues. In addition, the following reproduction/developmental parameters were determined: mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights, sex and macroscopy).

Positive control:

N/A

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily from treatment onwards up to the day prior to necropsy.
- Detailed clinical observations were made in all animals, immediately after dosing (on the peak period of anticipated effects after dosing). Once prior to start of treatment and at weekly intervals during the treatment period this was also performed outside the home cage in a standard arena. The time of onset, grade and duration of any observed sign was recorded. Signs were graded for severity and the maximum grade was predefined at 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) was scored.

BODY WEIGHT: Yes
- Time schedule for examinations: Males and females were weighed on the first day of exposure (prior to first exposure) and weekly thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum and during lactation on PND 1 and 4.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes /
- Time schedule for examinations: Weekly, except for males and females which were housed together for mating and for females without evidence of mating. Food consumption of mated females was measured on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum and on Days 1 and 4 of lactation.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

WATER CONSUMPTION: Yes
- Time schedule for examinations: Subjective appraisal was maintained during the study, but no quantitative investigated was introduced as no treatment related effect was suspected.

OPHTHALMOSCOPIC EXAMINATION: Not specified

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Time schedule for collection of blood: Blood samples were collected at the end of the treatment period, on the day of scheduled necropsy between 7.00 am and 10.30 am.
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Yes
- How many animals: 5/sex/group
- Parameter: White blood cells (WBC), Differential leucocyte count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), Red blood cells, Reticulocytes, Red blood cell distribution width (RDW), Haemoglobin, Haematocrit, Mean corpuscular volume (MCV), Mean corpuscular haemoglobin (MCH), Mean corpuscular haemoglobin concentration (MCHC), Platelets, Prothrombin time (PT), Activated partial thromboplastin time (APTT).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood samples were collected at the end of the treatment period, on the day of scheduled necropsy between 7.00 am and 10.30 am.
- Animals fasted: Yes (overnight)
- How many animals: 5/sex/group
- Parameters: Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), Alkaline phosphatase (ALP), Total protein, Albumin, Total bilirubin, Bile acids, Urea, Creatinine, Glucose, Cholesterol, Sodium, Potassium, Chloride, Calcium, Inorganic Phosphate.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

REPRODUCTION: Yes
Male number paired with, mating date, confirmation of pregnancy, and delivery day were recorded. Palpatation was used to aid in confirmation on pregnancy. Pregnant females were examined to detect signs of difficult or prolonged parturition, and cage debris of pregnant females was examined. Any deficiencies in maternal care (such as inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups or apparently inadequate lactation or feeding) were examined.

Sacrifice and pathology:

NECROPSY
All males and the selected 5 females/group were deprived of food overnight (maximum 24 hours) prior to planned necropsy, but water was provided. Non-selected females were not deprived of food. All animals surviving to the end of the observation period were deeply anaesthetised using isofluorane and exsanguinated and subjected to a full post mortem examination, with special attention being paid to the reproductive organs.

- Day of necropsy - males: Following completion of the mating period (minimum 28 days)
- Day of necropsy - females which delivered: Lactation days 6-7
- Day of necropsy - females which failed to deliver: Post-coitum days 25 or 27, respectively.

On the scheduled day of necropsy, terminal body weights were recorded from all males and the selected 5 females/sex/group.

GROSS PATHOLOGY: Yes
Samples of the following tissues and organs were collected and fixed in 10% buffered formalin (neutral phosphate buffered 4% formaldehyde solution): Adrenal glands, Aorta, Brain (cerebellum, midbrain, cortex (7 levels)), Caecum, Cervix, Clitoral gland, Colon, Coagulation gland, Duodenum, Epididymides, Eyes (optic nerve, Harderian gland), Female mammary gland area, Femur including joint, Heart, Ileum, Jejunum, Kidneys, Lacrimal gland, Larynx, Liver, Lung, Lymph nodes (mandibular, mesenteric), Nasopharynx, Esophagus, Ovaries, Pancreas, Peyer’s patches, Pituitary gland, Preputial gland, Postate gland, Rectum, Salivary glands (mandibular, sublingual), Sciatic nerve, Seminal vesicles, Skeletal muscle, Skin, Spinal cord (cervical, midthoracic, lumbar), Spleen, Sternum with bone marrow, Stomach, Testes, Thyroid including parathyroid, Tongue, Trachea, Urinary bladder, Uterus, Vagina and All gross lesions.

The Cervix, Clitoral gland, Coagulation gland, Epididymides, Female mammary gland area, Ovaries, Preputial gland, Prostate gland, Seminal vesicles, Testes, Uterus, Vagina and All gross lesions were also evaluated in female rats which failed to deliver.
Organ weights: Adrenal glands, Brain, Epididymides, Heart, Kidneys, Liver, Ovaries, Spleen, Testes, Thymus, Uterus (including cervix), Prostate, Seminal vesicles (including coagulating glands) and Thyroid (including parathyroid) were taken.

HISTOPATHOLOGY: Yes
- Preparation: Tissue samples were processed, embedded and cut at a thickness of 2-4 micrometers. These slides were stained with haematoxylin and eosin. The additional slides of the testes (to examine staging of spermatogenesis) were stained with PAS/haematoxylin.
- Parameters: Preserved organs and tissues of the selected 5 animals/sex of Groups 1 (control) and Group 4 (high dose), in addition to the thyroif gland, stomach and kidneys of all selected 5 males of Groups 2 and 3 and mesenteric lymph nodes of all selected 5 females of Groups 2 and 3, based on possible treatment-related changes in organs in Group 4.

Statistics:

The following statistical methods were used to analyse the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test was applied to frequency data.
- The Kruskal-Wallis nonparametric ANOVA test was applied to motor activity data to determine intergroup differences.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance.

Clinical signs:

no effects observed

Description (incidence and severity):

Alopecia was observed in one Group 2 female and two Group 3 females towards the end of the study. This finding occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under conditions in this study and was considered not to be a sign of toxicological relevance.

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weights and body weight gain of treated animals remained in the same range as controls over the treatment period.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Description (incidence and severity):

Food and water consumption before or after allowance for body weight was similar between treated and control animals.

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Haematological parameters of treated rats were considered not to be affected by treatment.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Increased levels of ALP were observed in females treated at 3 and 10 mg/kg bw/day, reaching a level of statistical significance at the high dose females, in comparison with controls. No toxicologically relevant changes occurred in the other clinical biochemistry parameters of treated male and female rats.

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

No effects on hearing ability, pupillary reflex, static righting reflex and grip strength were observed. For motor activity, in comparison with controls lower mean values for total movements as well as for ambulations were observed in treated males and females. Since all mean values for both parameters were within normal limits, and the control values at the upper end, the motor activity was considered not affected by treatment.
All groups shoed a similar habituation profile with a very high activity in the first interval that decreased over the duration of the test profile.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

In treated males, organ weights and organ to body weight ratios were considered to be similar to those of control animals. In treated females, a minimal tendency towards a dose-related increase in mean spleen weight was observed, achieving a level of statistical significance in the high dose females for absolute spleen weight, but not for spleen to body weight ratio. All individual spleen weights were within the normal range and, in the absence of histopathological changes in the spleen of these females, the changes were considered to be non-adverse. All other organ weights and organ to body weight ratios determined in females were similar to those in controls.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Macroscopic observations at necropsy did not reveal any alternations that were considered to have arisen as a result of treatment.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Test item-related microscopic findings were present in the thyroid gland of the 1, 3 and 10 mg/kg bw/day group males, the stomach of the 10 mg/kg bw/day males and the mesenteric lymph node of the 10 mg/kg bw/day females, and consisted of:
- Thyroid gland (males): a dose-related increase in incidence of minimal follicular cell hypertrophy which is regarded as an exacerbation of a spontaneous finding and as non-adverse.
- Stomach (males): mucosal hypertrophy of the glandular mucosa was noted in 2/5 of the 10 mg/kg bw/day males (up to slight degree). The hypertrophy was primarily present in the mucus cells of the foveolar epithelium and cells of the underlying proliferation zone and was without other test-item related stomach changes and therefore regarded as a local adaptive non-adverse change.
- Mesenteric lymph node (female): a subtle increase of sinusoidal erythrocytes (minimal) was observed in 10 mg/kg bw/day females. This was regarded as an exacerbation in a spontaneous finding and in absence of associated test-item related alterations of the gastrointestinal tract, as non-adverse.

One male treated with 1 mg/kg bw/day showed moderate germ cell depletion/degeneration atypical residual bodies and oligospermia of the testes with an abnormal spermatogenic profile and moderate luminal cell debris and oligospermia (=reduced sperm) of the epididymides, These lesions are regarded to be related with the lack of offspring. Based on the single occurrence in the low dose group, tis was considered as incidental and unrelated to treatment with the test item.

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Details on results:

The increased mean ALP-values observed in 3 and 10 mg/kg bw/day treated females, were the result of relatively high levels in some individual animals, rather than a group effect, as demonstrated by the relatively large standard deviation. In the absence of corroborative histopathological findings in relevant organs, the increases in ALP were considered to have occurred by chance and not to be related to treatment.

Minimal treatment related changes in splenic weight (females only) and in the histopathology of stomach, mesenteric lymph nodes (males only) and thyroid (females only) were recorded at the highest dose level of 10 mg/kg bw/day. The individual splenic weights were within the normal range and no histopathological changes were observed in the spleen in comparison with controls. The histopathological findings in the thyroid gland and mesenteric lymph node were regarded to be an exacerbation of spontaneous findings and the finding in the stomach was regarded as a local adaptive finding. Therefore, each of these changes observed at 10 mg/kg bw/day were considered to be non-adverse.

No treatment related changes were noted in any of the remaining parental parameters investigated in this study (i.e. clinical appearance, functional observations, body weight, food consumption, clinical laboratory investigations and macroscopic examination).

Key result

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical signs

mortality

Key result

Dose descriptor:

LOEL

Effect level:

3 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical biochemistry

Critical effects observed:

no

Lowest effective dose / conc.:

10 mg/kg bw/day (nominal)

Conclusions:

In a Combined 28-Day Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD 422), Potassium dicyanoargentate was administered to male and female Wistar Han rats (0, 1, 3 and 10 mg/kg bw/day) via oral gavage. No treatment related mortality or signs of overt toxicity were observed in any of the treatment groups. Based on the results, a No Observed Adverse Effect Level (NOAEL) of 10 mg/kg bw/day was derived.

Executive summary:

A subacute repeat dose toxicity study (28-days) is required to fulfil REACH Annex VIII information requirements. In a Combined 28-Day Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD 422), Potassium dicyanoargentate was administered to male and female Wistar Han rats (0, 1, 3 and 10 mg/kg bw/day) via oral gavage. Males were exposed for 2 weeks prior to mating, during mating, and up to termination (for 30 days). Females were exposed for 2 weeks prior to mating, during mating, the duration of pregnancy, and at least 5-6 days of lactation (for 42-46 days). Females which failed to deliver healthy offspring were exposed for 42 days.

An increase in mean ALP-values were observed in 3 and 10 mg/kg bw/day females, however, in the absence of corroborative histopathological findings, these increases were not considered to be related to treatment. Minimal treatment related changes in splenic weight (females only) and in the histopathology of stomach, mesenteric lymph nods (males only) and thyroid (females only) were recorded at the highest dose (10 mg/kg bw/day). However, the increase in splenic weight was within the historical control range and the histopathological findings in the thyroid and mesenteric lymph node were regarded to be an exacerbation of the spontaneous findings in the stomach. Therefore, the effects observed at the highest dose of 10 mg/kg bw/day were considered to be non-adverse. No treatment related changes were noted in any of the remaining parental parameters investigated in this study (i.e. clinical appearance, functional observations, body weight, food consumption, clinical laboratory investigations and macroscopic examination).

Based on the results in this combined 28-day repeated dose toxicity study with reproduction/developmental toxicity screening test, a No Observed Adverse Effect Level (NOAEL) of 10 mg/kg bw/day was derived.

The reproduction/developmental toxicity screening test (OECD 422) is an internationally accepted test method, as described in the Annex to the EU Test Methods (TM) Regulation (Council Regulation (EC) No 440/2008). Conducted according to the aforementioned guidelines and GLP, the study was considered to be reliable without restriction (Klimisch 1).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Klimisch 1 rated study (reliable without restrictions)

System:

other: General toxicity

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

In addition to the GHS and EU CLP 1272/2008 classification for skin corrosion (Category 1A), inhalation studies have also been waived based on dustiness data. Dustiness data for this substance showed that the respirable fraction (2.30 mg/g) is just 4.3% of the total inhalable fraction (52.94 mg/g) which leaves the majority (95.7%) which is not respired (sneezed or swallowed). These data reflect the particle size data (MMAD 34.9µm) when considering that respirable particles are usually under approximately 10 µm.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

In addition to the GHS and EU CLP 1272/2008 classification for skin corrosion (Category 1A), inhalation studies have also been waived based on dustiness data. Dustiness data for this substance showed that the respirable fraction (2.30 mg/g) is just 4.3% of the total inhalable fraction (52.94 mg/g) which leaves the majority (95.7%) which is not respired (sneezed or swallowed). These data reflect the particle size data (MMAD 34.9µm) when considering that respirable particles are usually under approximately 10 µm.

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

According to GHS and EU CLP 1272/2008 the test substance is classified as Category 1A for skin corrosion.

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

According to GHS and EU CLP 1272/2008 the test substance is classified as Category 1A for skin corrosion.

Additional information

In the general toxicity part of this OECD422 repeat dose toxicity and reproductive toxicity screening study, the dose levels of 1, 3 and 10 mg/kg/day demonstrated no treatment related signs of systemic toxicity. An increase in mean ALP-values were observed in 3 and 10 mg/kg bw/day females, however, in the absence of corroborative histopathological findings, these increases were not considered to be related to treatment. Minimal treatment related changes in splenic weight (females only) and in the histopathology of stomach, mesenteric lymph nodes (males only) and thyroid (females only) were recorded at the highest dose (10 mg/kg bw/day). However, the increase in splenic weight was within the historical control range and the histopathological findings in the thyroid and mesenteric lymph node were regarded to be an exacerbation of the spontaneous findings in the stomach. Therefore, the effects observed at the highest dose of 10 mg/kg bw/day were considered not to be adverse. No treatment related changes were noted in any of the remaining parental parameters investigated in this study (i.e. clinical appearance, functional observations, body weight, food consumption, clinical laboratory investigations and macroscopic examination).

Justification for classification or non-classification

There were no signs of toxicity at doses up to 10 mg/kg/day. Consequently, there were no toxicological changes considered supportive of a classification for specific organ toxicity following repeated exposure.